Chemoradiotherapy (CRT) and bio-radiotherapy (BRT) are recognized as standard therapies for head and neck cancer (HNC). Aspiration pneumonia after CRT or BRT is a common late adverse event. Our aim in this study was to evaluate the cause-specific incidence of aspiration pneumonia after CRT or BRT and to identify its clinical risk factors.
Trang 1R E S E A R C H A R T I C L E Open Access
Risk factors for aspiration pneumonia after
definitive chemoradiotherapy or
bio-radiotherapy for locally advanced head and
neck cancer: a monocentric case control
study
Sadayuki Kawai1, Tomoya Yokota1*, Yusuke Onozawa2, Satoshi Hamauchi1, Akira Fukutomi1, Hirofumi Ogawa3, Tsuyoshi Onoe3, Tetsuro Onitsuka4, Takashi Yurikusa5, Akiko Todaka1, Takahiro Tsushima1, Yukio Yoshida1,
Yosuke Kito1, Keita Mori6and Hirofumi Yasui1
Abstract
Background: Chemoradiotherapy (CRT) and bio-radiotherapy (BRT) are recognized as standard therapies for head and neck cancer (HNC) Aspiration pneumonia after CRT or BRT is a common late adverse event Our aim in this study was to evaluate the cause-specific incidence of aspiration pneumonia after CRT or BRT and to identify its clinical risk factors
Methods: We performed a retrospective analysis of 305 patients with locally advanced HNC treated by CRT or BRT between August 2006 and April 2015
Results: Of these 305 patients, 65 (21.3%) developed aspiration pneumonia after treatment The median onset was
161 days after treatment The two-year cause-specific cumulative incidence by CRT or BRT was 21.0% Multivariate analysis revealed five independent risk factors for aspiration pneumonia, namely, habitual alcoholic consumption, use
of sleeping pills at the end of treatment, poor oral hygiene, hypoalbuminemia before treatment, and the coexistence
of other malignancies A predictive model using these risk factors and treatment efficacy was constructed, dividing patients into low- (0–2 predictive factors), moderate- (3–4 factors), and high-risk groups (5–6 factors), the two-year cumulative incidences of aspiration pneumonia of which were 3.0, 41.6, and 77.3%, respectively Aspiration pneumonia tended to be associated with increased risk of death, although this was not statistically significant (multivariate-adjusted hazard ratio 1.39, P = 0.18)
Conclusion: The cause-specific incidence and clinical risk factors for aspiration pneumonia after definitive CRT or BRT were investigated in patients with locally advanced HNC Our predictive model may be useful for identifying patients at high risk for aspiration pneumonia
Keywords: Head and neck cancer, Aspiration pneumonia, Risk factor, Chemoradiotherapy, Case–control study
* Correspondence: t.yokota@scchr.jp
1 Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007
Shimonagakubo, Nagaizumi, Sunto-gun, Shizuoka 411-8777, Japan
Full list of author information is available at the end of the article
© The Author(s) 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver
Trang 2Chemoradiotherapy (CRT) is a standard treatment for
lo-cally advanced head and neck cancer (HNC) [1]
Radiother-apy (RT) with cetuximab, defined as bio-radiotherRadiother-apy
(BRT), is also considered as a treatment option for patients
with locally advanced HNC [2] Compared with radical
sur-gery, CRT and BRT have an advantage of preserving organ
function and patients’ quality of life; however, their
toxic-ities are not less harmful than the risks associated with
surgery In the previous clinical trial RTOG 91–11 [3],
non-cancer-related death was more common among patients
treated with CRT than with RT alone in a further
follow-up, despite the higher rates of laryngeal preservation [4]
This suggests that patients cured by CRT need appropriate
management against late toxicity
Aspiration pneumonia is recognized as pneumonia
secondary to the inhalation of food particles, saliva, or
gastric acid Patients with HNC who have undergone
definitive CRT tend to have swallowing dysfunction due
to mucositis during the treatment period or due to
radiation-induced fibrosis of the oropharyngeal
muscula-ture after completion of the treatment [5] Szczesniak et
al [6] reported that approximately 52% of patients who
received RT and 69% who received CRT suffered from
dysphasia after treatment, and aspiration pneumonia
accounted for 19% of non-cancer-related deaths
Add-itionally, Xu et al [7] suggested that aspiration
pneumo-nia was a poor prognostic factor for patients with HNC
who received CRT Therefore, clinicians should assess
the risk of aspiration pneumonia in order to identify
pa-tients for whom efforts to prevent it should be
implemented
The purpose of this study was to identify clinical risk
factors for aspiration pneumonia after definitive CRT or
BRT for patients with advanced HNC In particular, we
focused on the cause-specific incidence of aspiration
pneumonia, taking competing events of death and
resec-tion of the primary lesion into account
Methods
Study population
Three hundred and forty patients with HNC who
re-ceived definitive concurrent CRT or BRT at Shizuoka
Cancer Center between August 2006 and April 2015
were identified from medical records Of these, 35
pa-tients with a recurrent or metastatic lesion or resection
of the primary lesion before CRT were excluded
Pa-tients with other malignancies were included only if
HNC was considered to be the factor most strongly
de-termining their prognosis Finally, 305 patients were
in-cluded in this analysis This study was approved by the
Institutional Review Committee of Shizuoka Cancer
Center (Shizuoka, Japan) and met the standards set forth
in the Declaration of Helsinki
Study covariates
We retrospectively collected data on the occurrence of as-piration pneumonia, time to onset of asas-piration pneumonia, and overall survival (OS) from the end of treatment Back-ground covariate candidates for factors predictive of aspir-ation pneumonia included the following: tumor site, age, gender, Eastern Cooperative Oncology Group (ECOG) per-formance status, body mass index, TNM staging according
to the AJCC/UICC TNM classification, tumor histology, smoking status, habitual alcoholic consumption, distance between the patients’ home and the hospital, family mem-bers in the same household, use of proton pump inhibitors (PPIs) or H2 blockers, use of angiotensin-converting en-zyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), use of sleeping pills and main feeding at the end of the treatment, presence of gastrostomy during the treat-ment, oral hygiene, serum albumin (ALB) and hemoglobin (Hb) levels before treatment, coexistence of other malig-nancies before treatment, and Charlson comorbidity index
We defined habitual alcoholic consumption as the drinking
of alcohol four or more days a week, and poor oral hygiene
as the presence of moderate or more severe dental plaque assessed by a dentist and/or a dental hygienist Charlson co-morbidity index is a tool for predicting mortality by classi-fying or weighting comorbidities [8]
We also collected the following treatment-related covar-iate data: presence or absence of induction chemotherapy, chemotherapy regimen, irradiation technique [conven-tional three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT)], irradiation field, treatment efficacy evaluated according to Response Evaluation Criteria in Solid Tumors ver 1.1 [complete response (CR) or non-CR], mucositis and dys-phagia during treatment evaluated by Common Termin-ology Criteria for Adverse Events ver 4.0, and decreases
of ALB, Hb, and body weight after treatment
Aspiration pneumonia
Because it is sometimes difficult to clearly distinguish as-piration pneumonia from other types of pneumonia, dif-ferent definitions of aspiration pneumonia were used in previous studies [9–11] Therefore, in this study, we de-fined aspiration pneumonia as a clinical condition that met all of the following criteria: (i) Patients had both subjective and objective symptoms suggesting pneumo-nia Subjective symptoms included wet cough, sputum, and fever Objective symptoms included the presence of coarse crackles in the chest, elevated inflammatory markers (e.g white blood cell count or C-reactive pro-tein), or image findings (e.g infiltration on a chest X-ray
or consolidation in chest computed tomography) (ii) The presence of aspiration was suspected clinically (choking or delayed swallowing) or by endoscopic or video-fluorographic examinations (iii) No evidence of
Trang 3micro-organisms that cause atypical pneumonia, such as
Legionella and Mycoplasma
Statistical analysis
The cause-specific cumulative incidence of aspiration
pneumonia was estimated with nonparametric cumulative
incidence functions, taking competing events of death and
resection of the primary lesion into account To
investi-gate potential risk factors for aspiration pneumonia,
uni-variate analysis was carried out for all couni-variates using
Fisher’s exact test, and covariates showing statistical
sig-nificance were further analyzed using a multivariate
logis-tic regression model To construct a predictive model, we
automatically selected covariates extracted from univariate
analysis, and compared the goodness-of-fit among many
models on the basis of the stepwise Akaike information
criterion (AIC) method [12] The minimum value from
the AIC procedure allows us to select appropriate
pre-dictive factors to construct an optimal prepre-dictive model
objectively The concordance index to evaluate the
dis-criminatory ability of the model was calculated using the
final regression model [13]
The OS time was calculated from the date of
treat-ment end to the date of death due to any cause or to the
last date of confirmed survival Survival rates were
esti-mated using the Kaplan–Meier method To estimate the
association of covariates with overall survival, univariate
analysis was carried out using the log-rank test All
sta-tistically significant covariates in univariate analysis were
analyzed in multivariate analysis using the Cox
regres-sion model
All statistical tests were two-sided, and P≤ 0.05 was
considered significant Statistical analyses were
per-formed using EZR software (Saitama Medical Center,
Jichi Medical University, Saitama, Japan) [14]
Results
Among the 305 patients, 65 (21.3%) developed aspiration
pneumonia after CRT or BRT Patients’ baseline and
treatment-related characteristics are summarized in
Table 1 The median age of the patients was 65 years
(range 19–83) and 95.1% of them had ECOG PS of 0 to
1 Cisplatin, carboplatin, and cetuximab were
concur-rently used in 77.1, 13.7, and 9.2% of patients,
respect-ively Seventy-six (24.9%) of the patients received
induction chemotherapy, and 87.5% of them were
treated with the combination of docetaxel, cisplatin, and
fluorouracil Additionally, 96.0% of all patients had
re-ceived systematic oral care [15] since initiation of the
treatment Thirty-six (11.8%) patients had coexisting
ma-lignancies included multiple primary HNC, esophageal
cancer, gastric cancer, prostate cancer, lung cancer, and
renal cancer All of these cancers were found at an early
stage by routine endoscopic or computed tomography
screening After definitive CRT or BRT, 30 (9.8%) pa-tients underwent resection of the primary lesion and 45 (14.7%) underwent neck dissection for a residual lesion
or recurrence
The median time from the end of treatment to aspir-ation pneumonia events was 161 days (range 3–1623) The median follow-up time was 892 days The two-year cumulative incidences of aspiration pneumonia and competing events of death and resection of the primary lesion were 21.0% [95% confidence interval (CI) 16.4– 26.0%], 12.9% (9.2–17.4%), and 6.2% (3.7–9.5%), respect-ively (Fig 1)
Univariate and multivariate analyses identified five inde-pendent risk factors for aspiration pneumonia, namely, habitual alcoholic consumption, poor oral hygiene, coex-istence of other malignancies, hypoalbuminemia before treatment, and the use of sleeping pills at the end of treat-ment (Table 2) A difference in the types of sleeping pills (benzodiazepines or others) used was not associated with the onset of aspiration pneumonia (odds ratio 0.95, 95%
CI, 0.37–2.39, P = 1.00) Of 193 patients with poor oral hy-giene before treatment, 135 had been followed up by den-tists three months after the treatment In total, 87 of 135 patients in whom oral hygiene had improved three months after the treatment had a significantly lower fre-quency of aspiration pneumonia than 48 patients who had poor oral hygiene (18.3% vs 54.1%, P = 0.00003)
Next, we attempted to construct a predictive risk model of aspiration pneumonia from the results of uni-variate analysis As a result of AIC stepwise selection, six predictive factors, consisting of the five risk factors ex-tracted from the multivariate analysis and treatment effi-cacy (non-CR), were selected Although treatment efficacy was not identified as a statistically significant risk factor, AIC stepwise selection revealed that it was a good predictive factor for the model This predictive model well divided patients into low- (0–2 factors, n = 180), moderate- (3–4 factors, n = 103), and high-risk groups (5–6 factors, n = 22) by the number of predictive factors, for which the estimated two-year cumulative in-cidences of aspiration pneumonia were 3.0% (95% CI, 1.1–6.5%), 41.6% (31.0–51.8%), and 77.3% (51.4–90.5%), respectively (Fig 2) The concordance index was 0.797 Finally, we investigated the correlation between OS and the occurrence of aspiration pneumonia Survival curves adjusted for the covariates from a Cox propor-tional hazard model indicated that the occurrence of as-piration pneumonia tended to be associated with the risk of death, but this was not statistically significant (hazard ratio, 1.39; 95% CI, 0.85–2.27; P = 0.18) (Fig 3)
Discussion
The important goals of treatment in patients with HNC are not only a cure but also the preservation of quality
Trang 4Table 1 Patients’ characteristics
Age
Gender
ECOG performance status
Body mass index
Primary site
T-classification
N-classification
Tumor histology
Smoking status
Habitual alcoholic consumption
Table 1 Patients’ characteristics (Continued)
Distance from the hospital
Family members in the same household
Use of ACEi or ARB
Use of PPI or H 2 blocker
Oral hygiene before treatment
Coexistence of other malignancies
Comorbidity index
Serum albumin before treatment
Hemoglobin before treatment
Use of sleeping pills at the end of treatment
Main feeding at the end of treatment
Presence of gastrostomy during the treatment
Induction chemotherapy
Concurrent chemotherapy regimen
Trang 5of life post-treatment Although approximately 60–70%
of patients with HNC treated with CRT suffer from dys-phagia or aspiration as a late toxicity [16, 17], in previ-ous studies, the incidence of aspiration pneumonia within a year after CRT was found to differ, ranging from 5.4 to 23% [9, 17, 18] Furthermore, no differences
in the frequency of aspiration pneumonia were seen be-tween the different observation periods, despite the im-provement of radiation techniques and general management of CRT over the time This suggests that various factors other than aspiration are associated with the occurrence of aspiration pneumonia
To clarify the population at high risk of aspiration pneumonia after CRT or BRT, we investigated the tors predictive of aspiration pneumonia Several risk fac-tors for aspiration pneumonia in patients with HNC after CRT were reported in previous studies [7, 9, 17] However, evaluation of the long-term risk factors was often difficult in patients with HNC because these pa-tients’ characteristics varied according to the multimodal therapies that they had received, including surgery, CRT, and RT In particular, previous studies did not take sal-vage surgery after CRT into account Therefore, in these studies, there might not have been accurate estimates of the treatment-specific incidence of aspiration pneumo-nia after CRT To our knowledge, the current study is the first regarding specific risk factors and predictive models for aspiration pneumonia as a late toxicity in pa-tients with HNC undergoing definitive CRT or BRT
We intended to determine risk factors for aspiration pneumonia after CRT or BRT by estimating the cause-specific cumulative incidence To do this, we first per-formed cumulative incidence analysis, and regarded
Table 1 Patients’ characteristics (Continued)
Radiation technique
Irradiation field
Treatment efficacy
Body weight loss after treatment
Serum albumin decreasing post-treatment
Hemoglobin decreasing post-treatment
The worst mucositis grade during treatment
The worst dysphagia grade during treatment
Resection of primary lesion post-CRT or -BRT
Neck dissection post-CRT or -BRT
Abbreviations: ECOG Eastern Cooperative Oncology Group, SCC Squamous cell
carcinoma, ACEi Angiotensin-converting enzyme inhibitor, ARB Angiotensin II
receptor blocker, PPI Proton pump inhibitor, 3D-CRT Three-dimensional
conformal radiation therapy, IMRT Intensity-modulated radiation therapy, CR
Complete response, CRT Chemoradiotherapy, BRT Bio-radiotherapy
The normal range of laboratory data at our institution: Serum albumin (3.8–
5.2 g/dl), hemoglobin (male: 13.5 –17.6 g/dl, female: 11.3–15.2 g/dl)
Fig 1 Cumulative incidence of aspiration pneumonia and other competing risks including death and resection of primary lesion Vertical dashes indicate censored observations
Trang 6Table 2 Univariate and multivariate logistic regression analyses for risk factors of aspiration pneumonia
Age
Gender
ECOG performance status
Body mass index
Primary site
T-classification
N-classification
Tumor histology
Smoking status
Habitual alcoholic consumption
Distance from the hospital
Family members in the same household
Trang 7Table 2 Univariate and multivariate logistic regression analyses for risk factors of aspiration pneumonia (Continued)
Use of ACEi or ARB
Use of PPI or H 2 blocker
Oral hygiene before treatment
Coexistence of other malignancies
Comorbidity index
Serum albumin before treatment
Hemoglobin before treatment
Use of sleeping pills at the end of
treatment
Main feeding at the end of treatment
Presence of gastrostomy during the
treatment
Induction chemotherapy
Concurrent chemotherapy regimen
Radiation technique
Irradiation field
Trang 8Table 2 Univariate and multivariate logistic regression analyses for risk factors of aspiration pneumonia (Continued)
Treatment efficacy
Body weight loss after treatment
Serum albumin decreasing
post-treatment
Hemoglobin decreasing
post-treatment
The worst mucositis grade
during treatment
The worst dysphagia grade
during treatment
Abbreviations: ECOG Eastern Cooperative Oncology Group, SCC Squamous cell carcinoma, ACEi Angiotensin-converting enzyme inhibitor, ARB Angiotensin II receptor blocker, PPI Proton pump inhibitor, 3D-CRT Three-dimensional conformal radiation therapy, IMRT Intensity-modulated radiation therapy, CR Complete response The normal range of laboratory data at our institution: Serum albumin (3.8–5.2 g/dl), hemoglobin (male: 13.5–17.6 g/dl, female: 11.3–15.2 g/dl)
Fig 2 The estimated cumulative incidence of aspiration pneumonia according to the number of predictive factors Vertical dashes indicate censored observations
Trang 9resection of the primary lesion as a competing event.
Surgical procedures clearly affect swallowing function
For example, total laryngectomy reduces the risk of
as-piration and head and neck reconstruction changes
pa-tients’ ability to swallow [19, 20] Therefore, surgical
intervention after CRT/BRT may obscure the association
of aspiration with CRT or BRT On the other hand, the
effect of neck dissection on aspiration pneumonia has
been controversial For instance, Lango et al [21]
re-ported that radical neck dissection (RND) increased the
risk of feeding tube dependence in patients with HNC
who underwent RT or CRT On the other hand, Chapuy
et al [22] reported that types of neck dissection
includ-ing RND, modified RND, and selective neck dissection
(SND) did not aggravate swallowing function In this
study, 45 patients underwent neck dissection, 44 (97%)
of which underwent SND Our analysis suggested no
sig-nificant association between neck dissection and the
oc-currence of aspiration pneumonia (P = 0.23) Therefore,
we did not consider neck dissection as a competing
event in cumulative incidence analysis
Consistent with previous reports [23],
hypoalbumin-emia was again identified as a factor predictive of
aspir-ation pneumonia after CRT and BRT in our study The
novel predictive factors identified here were poor oral
hygiene, use of sleeping pills, coexistence of other
malig-nancies, and habitual alcohol consumption
Several studies have demonstrated that careful oral
management could reduce the risk of aspiration
pneu-monia in elderly people and patients with a history of
cerebral infarction [24, 25] However, few studies have
focused on the correlation between oral hygiene and the
risk of aspiration pneumonia in patients with HNC At our institution, patients with HNC undergoing RT have been routinely referred to dentists and received system-atic oral care during the treatment [15] Indeed, 96.0% of patients received oral evaluation before treatment in this cohort However, 35.6% of patients initially evaluated as having poor oral hygiene were still assessed as having this same status after the treatment This suggested that continuous oral management is required in high-risk pa-tients, even after treatment
Previous studies suggested that sleeping pills increased the risk of aspiration pneumonia [26, 27] Among these, benzodiazepines were especially associated with the in-duction of aspiration through gamma-amino-butyric acid type A (GABA-A) signaling in the lesser esophageal sphincter, in addition to inhibition of the central nervous system [28] However, in our study, benzodiazepines did not specifically increase the risk of aspiration pneumonia more than other sleeping pills Notably, 83 out of 94 (88.3%) patients who used sleeping pills at the end of the treatment continued to use them even after the treat-ment Al-Mamgani et al [29] demonstrated that 30.7%
of patients with nasopharyngeal cancer who received RT
or CRT had the complaint of insomnia during the treat-ment; however, approximately half of them recovered after the treatment These findings suggest that the un-necessary administration of sleeping pills might increase the risk of aspiration pneumonia for our patients Our data demonstrated that the coexistence of other malignancies was a risk factor for aspiration pneumonia
Of 11 patients who had multiple primary HNC or cer-vical esophageal cancers simultaneously treated by CRT with main HNC, 7 (63.6%) developed aspiration pneu-monia A previous report suggested that enlargement of the irradiation field increased the risk of aspiration pneumonia [30] Furthermore, 18 patients underwent surgical or endoscopic resection for esophageal and gas-tric cancer Of these, six (33.3%) developed aspiration pneumonia, three of whom developed it within one week resection Therefore, we speculated that post-surgical immunosuppression and anesthesia or sedation before endoscopy might deteriorate swallowing function Previous reports indicated that alcohol suppressed the cough reflex, reduced consciousness, and promoted gastro-esophageal reflux [31–33] Therefore, such com-plex factors induced by habitual alcohol consumption may be involved in the occurrence of aspiration pneumonia
Scheld et al [34] and Xu et al [7] reported that aspir-ation pneumonia was a significant prognostic factor Furthermore, Szczesniak et al [6] reported that aspir-ation pneumonia accounted for 19% of non-cancer-related deaths of patients with HNC who received CRT Therefore, we expected that aspiration pneumonia
Fig 3 Adjusted Kaplan –Meier curve illustrating overall survival from
the date of the end of the treatment among patients with head and
neck cancer who received chemoradiation or bio-radiation therapy
stratified according to whether or not they developed aspiration
pneumonia Vertical dashes indicate censored observations CI:
confidence interval, HR: hazard ratio
Trang 10would be strongly associated with patient survival
How-ever, our study did not show a statistically significant
dif-ference in survival between patients who developed
aspiration pneumonia and those who did not, probably
because of the relatively small number of deaths within
the short follow-up period
Our study had several limitations First, it involved a
retrospective analysis at a single institution Second,
dif-ferential diagnosis between aspiration pneumonia and
other types of pneumonia was often difficult because the
definitions of aspiration pneumonia varied among
previ-ous reports [9–11] Third, the median follow-up of
2.4 years was shorter than in previous studies [4, 7] The
ability of our predictive model might change upon a
long-term follow-up For example, because submucosal
remodeling and neurological disturbance slowly progress
after irradiation [35], irradiation might have a stronger
impact on the occurrence of aspiration pneumonia at a
later phase
Further studies are warranted to validate our predictive
model because of the retrospective nature of this study
However, the strength of our study is that almost all
pa-tients received standard chemotherapeutic regimens
con-taining platinum or cetuximab, with systematic supportive
care such as oral care Therefore, our predictive model
may be more useful for identifying patients at high risk for
aspiration pneumonia in recent clinical practice than
pre-vious evidences For example, we propose that clinicians
consider swallowing exercises for high- or moderate-risk
groups to improve their swallowing function and
subse-quently prevent aspiration pneumonia [35]
Conclusions
We investigated the cause-specific incidence and
identi-fied risk factors for aspiration pneumonia following
de-finitive CRT or BRT for patients with locally advanced
HNC The prediction of aspiration pneumonia may be
necessary to preserve the quality of life and extend life
expectancy for patients Long-term follow-up and
fur-ther prospective studies are needed to validate the
use-fulness of our predictive model
Abbreviations
3D-CRT: Three-dimensional conformal radiation therapy; ACE:
Angiotensin-converting enzyme; AIC: Akaike information criterion; ALB: Serum albumin;
ARBs: Angiotensin II receptor blockers; BRT: Bio-radiotherapy; CR: Complete
response; CRT: Chemoradiotherapy; ECOG: Eastern Cooperative Oncology
Group; GABA-A: Gamma-amino-butyric acid type A; Hb: Hemoglobin;
HNC: Head and neck cancer; IMRT: Intensity-modulated radiation therapy;
OS: Overall survival; PPIs: Proton pump inhibitors; RND: Radical neck
dissection; RT: Radiotherapy; SND: Selective neck dissection
Acknowledgements
Not applicable.
Funding
None.
Availability of data and material The data analyzed during the current study are available from the corresponding author on reasonable request.
Authors ’ contributions Conceptualization: SK, Writing an original draft: SK, Project administration: TY, Review and editing: TY, YO, AF, Formal analysis: KM, Supervision: HY, Investigation of data: SK, TY, SH, HO, TO, TO, TY, AT, TT, YY, YK, and All authors read and approved the final manuscript.
Competing interests The authors declare that they have no competing interests.
Consent for publication Not applicable.
Ethics approval and consent to participate This study was approved by the Institutional Review Committee of Shizuoka Cancer Center (Decision number 27-J104-27-1) and met the standards set forth in the Declaration of Helsinki Authors obtained written informed con-sent from the participants If it was difficult to get, authors provided the in-formation of this study and patients ’ right on the website or in a notice board at the hospital.
Author details
1 Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi, Sunto-gun, Shizuoka 411-8777, Japan.2Division
of Medical Oncology, Shizuoka Cancer Center, Sunto-gun, Shizuoka, Japan.
3
Division of Radiation Oncology and Proton Therapy, Shizuoka Cancer Center, Sunto-gun, Shizuoka, Japan 4 Division of Head and Neck Surgery, Shizuoka Cancer Center, Sunto-gun, Shizuoka, Japan.5Division of Dental and Oral Surgery, Shizuoka Cancer Center, Sunto-gun, Shizuoka, Japan 6 Clinical Research Center, Shizuoka Cancer Center, Sunto-gun, Shizuoka, Japan Received: 26 August 2016 Accepted: 10 January 2017
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